The long-term goal of this proposed research project is to establish a high-resolution noninvasive 3- dimensional electrocardiographic imaging (3-DEIT) methodology that can noninvasively map cardiac electrical activity within the 3-dimensional (3-D) heart. Sudden death from ventricular tachycardia (VT) and ventricular fibrillation claims over 400,000 lives each year in the United States alone. Development of effective imaging technologies is critical in the evolution of interventional (and potentially pharmacologic) approaches to prevent and treat these malignant arrhythmias. Noninvasive mapping of activation sequence and localization of sites of origin of arrhythmia would thus be of enormous value for numerous patients. The ultimate goal of the proposed research project is to establish and validate a novel 3-D cardiac electrical imaging approach that has been pioneered by the PI which is able to image the activation sequence over the 3-D myocardium from noninvasive body surface potential maps. Although solving the cardiac inverse problem in 3-D translates into severe underdetermined nature in the inverse problem, the proposed use of a heart excitation model, in which cardiac electrophysiological knowledge is incorporated, will redefine this relationship. Also novel to the proposed research is rigorously validating the proposed 3- DEIT in a closed-chest animal model as assessed by 3-D intracardiac mapping. Our preliminary results in an animal model, that demonstrate reconstruction of activation sequence throughout the 3-D myocardium from noninvasive body surface potential measurements and computer tomography images (as tested with 3-D intracardiac mapping), attest to the feasibility of the proposed studies. The specific aims of the proposed project are: Aim 1) To develop 3-D electrocardiographic imaging methods and evaluate it in computer simulations; Aim 2) To validate 3-D electrocardiographic imaging in vivo during ventricular pacing using 3-D intracardiac mapping in the rabbit heart; and Aim 3) To validate 3-D electrocardiographic imaging during ventricular tachycardia in rabbits with experimentally-induced heart failure. The successful completion of the proposed research would enable us to establish a novel noninvasive cardiac functional imaging methodology that could define initiation sites, activation sequences (and potentially arrhythmogenic mechanisms) for pathologic arrhythmias (which is currently not possible). The results of this work would also provide the critical foundation for establishing the proposed 3-DEIT as a novel tomographic imaging modality to guide catheter ablation of arrhythmias, and to develop and to assess the effects of new therapeutic approaches targeted to specific arrhythmia mechanisms for the treatment of VT in patients with heart failure (and other cardiac diseases). [unreadable] [unreadable] [unreadable]